- Dr Rajashree Devarakonda, Voisin Consulting Life Sciences
The Indian Clinical Trial
Industry, considered as
the booming sector and
perceived as a potentially
upcoming segment,
is undergoing turmoil
today with a decline of
9.60 per cent in revenues,
with further decline because
of delay/decreased clinical
trial approvals.

India was considered as one of the hubs
for conducting major global multinational
clinical trials. It still has the potential
to establish itself as a hub for global
Clinical Trials (CTs). There are several
reasons to it, including but not limited to
– a large treatment naďve population with
diversity in the gene pool with a range of
illnesses, many easily accessible tertiary
care hospitals, relatively lower cost of
clinical trials compared to the western
countries, high enrolment rates, good
patient compliance/retention, ICH GCP
trained healthcare professionals (HCPs),
a generation of gifted young medical
students, scientists and researchers
who are eager to contribute valuably to
the advancement of medical science,
availability of trained man power and
infrastructure and fairly accommodative
regulatory environment at least until now.

However, the current scenario tells us a
different story. The recent amendments
to regulation, has contributed to a decline
in the Indian Clinical Trial Industry. There
are several challenges that the sponsor
companies are facing which are diverting
them to conduct their trials in countries like China and Taiwan as they are disillusioned
with the uncertain regulatory environment
here. As well, many companies are as
well going for locations like US, European
Union, Canada and Malaysia going by
the expertise and speedy clearances,
which will be cheaper in the long run.
Recently few academic NIH trials were
also put on hold by US NIH. This trend
is a big dent to the Indian CT sector.
According to the research firm Frost and
Sullivan, the CTs business in India is
estimated to be worth around USD 500
million, which projects that it will grow to
USD 1 billion by 2016. However, the
industry experts have estimated a loss of
USD 150-200 million in the past six months
due to the changes in the regulations.
We will have to wait to see if this is
still achievable.

Recent Amendments to Drug and
Cosmetic Rules
In India, Central Drugs Standard Control
Organisation (CDSCO) (headed by Drug
Controller General of India) is the primary
authority and "Drugs and Cosmetics Act,
1940" (along with the rules framed there under) is the principal legislation for the
regulation of CTs. Schedule Y of the Drugs
and Cosmetics Rules (DCR), 1945 provides
Rules relating to CTs in India.

Since last few years, it was required on
the part of the DCGI to formulate new
regulations or modify the existing ones in
order to streamline the CT process in India.
Recently, in January 2013, DCGI amended
the DCR 1945 to bring the following three
amendments. Few examples of each
amendment are provided as well:

These amendments have brought sudden
change to the CT regulations. Many of
these amendments were long overdue and
were very much required however without
too many lacunas and should have been
done in consultation with the stakeholders
especially while finalising the amendments
(Public, Sponsors, CROs, Academia, Ethics
Committees, Regulators and Ministry) to
avoid the anguish that the CT industry is
undergoing currently.

The amendment has brought in several
good changes (EC/CRO registration, GCP
Compliance and other related quality
changes), as well as challenges. Bringing
these amendments is laudable. However,
the current regulation is leaning primarily
to guard the safety of trial participants
and to improve the much criticised with
a justifiable reason, inefficiencies of
several Clinical research players including
CROs, investigators, ECs, regulators and
sponsors in managing properly ethically
compliant CT process.

Hence, revision of the regulation was very
much needed and is much welcomed after
years of well-documented ethical lapses
in few cases, including informed consent
issues, protocol violations, compensation
issues by the sponsors among others.
Although the DCGI has made an effort to bring some stringent regulations and to
create a structure similar or stricter than
few regulated countries, there still are
many lacunas in these amendments.

Challenges/Gaps in the Recent
Amendment(s)
The language of regulation itself is
ambiguous at places and has loopholes,
which needs to be clarified.

• Compensation for “any injury” or
death during CTs due to failure of
investigational product to provide the
intended therapeutic effect and use of
placebo in a placebo controlled trial.
Medical coverage and compensation
for any type of injury whether it is
related or not is a major issue, and
there is no clarity for how long and
how much compensation need to be
provided which will be decided by the
regulatory authority and ECs on a case
by case basis. If this compensation
is not provided, this may lead to the
company suspending/losing the license
to conduct CT in India on a case-bycase
basis. This is acting as a deterrent
for many pharma MNCs.

The investigator’s obligation to report
any SAE with 24 hours of the occurrence
of the event is practically impossible as
such information might not be available
in the mentioned time period.

The sponsor needs to report any SAE
of death to EC and expert committee
within 10 days of occurrence, while it is
14 days as per international practice.

21 calendar day timeline for EC to
provide opinion on SAE as well as
financial compensations.

The timelines for EC to examine the SAE
of death and for DCGI to determine the
cause of injury/death are 30 days and 90
days respectively, which looks arbitrary.

The amendments again fail to address
issue of variable timelines for CT approval leading to significant delays
and lost trust for the sponsor companies.

Challenges of Conducting CTs in India
in General1) Ethical issuesa. Even though, India has the manpower,
experienced HCPs and infrastructure
to handle more CTs, ethical oversight
is somewhat missing. International
companies are losing trust in the Indian
institutes, as there have been cases of
unethical practices in the past.

b. Until now, the ECs were not required
to register with the DCGI. This led to
independent working of the ECs leading
to in few cases frauds and manipulation
of trial data.

c. Another important challenge lies with
the protection of rights of the subjects
in the CTs.

d. No transparency in informed consent
processing.

e. Involvement of major sub group of
vulnerable population (illiterates,
Villagers with lack of awareness,
pregnant women and children) in trials
leading to in few cases exploitation of
the subjects.

c."Laissez faire" attitude leading to taking
lightly some of the key ethical steps in
CTs including improper documentation.

3) Regulatory issues
a. Delays/Lack of CT approvals: could be
mainly due to shortage of technical/
trained staff.

b. Lack of standardisation and
transparency in CT approvals/audits/
inspections and reason for decisions.

4) Cultural issues
a. In India, the personal physician
strongly influences patient decisions,
as do family and friends, which could
raise potential ethical issues with
patient recruitment unless the process
is transparent.

b. Informed consent needs to be in local
language. This means translation needs
to be performed in multiple languages.

5) Media
a. There has been lot of negative publicity
of CTs in India by media sometimes
with biased/inaccurate data on safety
related to CTs, which has led to overall
negativity/uncertainties in subjects,
industry and government leading to
development of laws, which are very
restrictive rather than supportive.

6) Training/Mentoring
a. Lack of practical advanced GCP and
CT training of HCPs including regular
up gradation and or maintenance of
certification is a major issue.

b. India has an extraordinary pool of
bright, insightful young medical talent
who are often given minimal guidance
and mentorship, and even less financial
support in their endeavors leading to
waste of talent.

Overcoming the Challenges
It is the hope of the clinical trial industry
stake holders that the recent amendments
to the regulations once lacunas are
addressed should be able to address many
of the following critical steps leading to
solutions to protect the integrity of Indian CT industry leading to India back on as a
global hub for global CTs.

The amended regulations are great even
though very stringent in few aspects
and were needed for Mandatory GCP
compliance, mandatory AE reporting, EC/
CRO/CT registration including mandatory
compensation for the subjects. However,
the ambiguity in the regulations has to be
clarified soon, as these regulations look
more patient/subject friendly and lesser
sponsors friendly so that there is a balance
in the regulation enabling researchers
to conduct CTs in India with integrity as
ethically conducted CTs are very much
necessary for drug discovery and treatment
of rare complex diseases in India or globally.

Compensation and safety reporting
amendments specially need to be
revisited. Compensation should be limited
to the injury or death of the subject, which
are resulting directly or justifiably related
to the participation of the subjects in the
CTs and it should not be for unrelated
events or any injury. There should be
clarity on the compensation amount to be
reimbursed. It is important that medical
treatment for trial related injury should be
covered by the sponsors.

However, there should be more clarity on
the amount of compensation to be given, for how long the medical treatment should
be given, and industry also should be able
to participate in this calculation along
with DCGI and ECs. There is urgency in
this matter, as we have already seen a
decline in the number of CTs in India since
last year and companies moving their
base to other countries. Positive note is
that, the Drug Technical Advisory Board
(DTAB), in their recent meeting on May
16th, 2013, has proposed few changes to
these amendments which are still under
discussion. For example: including the
words “In the case of CT related injury” in
the compensation clause to bring clarity
that only trial related death/injury needs
to be compensated for. Although they
have not commented on the amount of
compensation to be provided, they have
recommended that a qualifying clause may
be added “in case there is no permanent
injury, the quantum of compensation shall
commensurate with the inconvenience,
loss of wages, transportation”. The
DTAB has recommended the removal of
the compensation for the failure of the
investigational drug for intended therapeutic
effect as well; they have added the clause
use of placebo in a placebo controlled trial
“if the standard care is denied”.

As discussed earlier, the timelines for
SAE reporting are also a major concern
and needs to be revised. For example,
modifying the timelines to meet the
international standards : 14 days instead of
10 days for sponsors and investigators, 30
days (instead of 21) for ECs to report SAE,
60 days (instead of 30) Expert committee
to examine SAE and 60 days (instead of
90) for the DCGI to determine the cause of
injury and decide quantum of compensation.
These are few recommendations that the
DTAB has provided during their meeting
in May. This might help to streamline the
timelines and reduce the ambiguity in the
regulations. However, it needs to be noted
that these are only recommendations at
this stage and are not approved yet.

It is crucial to increase the technical staff
with advanced industry training at the DCGI
office as they are currently understaffed/
undertrained which leads to delays in
approval of CTs. Further training by
international regulator exchange programs as well as advanced training in clinical
trial design, implementation, monitoring,
data management, and quality assurance
including funding the DCGI’s office might
help to improve the consistency of approvals,
reduce the time taken for approvals and
thereby increase the trust factor of the MNCs
in the Indian regulatory system.

Once this is concluded, providing more
power to DCGI’s office to make the decisions
might be useful. As well, planned setting up
of technical and regulatory expert committee
to support CT application filing, review and
related activities should take a priority and
be established soon to streamline these
activities. Streamlining of, and improved
cross-communication and cooperation
between the other agencies involved in the
CT process approvals will be useful.
ECs need to be linked to Institutes, should
have appropriate representatives and
ideally should be monitored centrally.
Constant monitoring and accountability
of the ECs as well is the key to ensure
quality ethical operation. ECs should do
proper monitoring of trials including the
consenting aspects, ensuring the diversity
of trial populations so as to avoid misuse of
vulnerable population including recruitment
of poor homogeneous rural communities.

CROs when not meeting ICH GCP
quality and ethical standards should be
removed. A barrier needs to be created
between industry and CT investigators to
ensure ethical conduct of research. CROs
should conduct trials to the internationally
recognised standards by conformance to
CT protocol and independent monitoring.
Independent research in private clinics
without supervision should not be allowed.
There should be transparency at all levelssponsors,
CROs, Investigators, Regulators
and ECs. Sponsors should ensure
registration of all CTs in the CTs registry.
Sponsors should also communicate risks/
benefits of the trials including safety issues
related to the drug/device including trial
related risks to all the subjects including
vulnerable population. Investigators
should be transparent about the treatment
given, adverse events, relatedness to
the trial activities etc. with the public and
regulators. Informed consent process need
to be highly transparent and it should be
voluntary and documented properly.
Transparency by the regulators in the
entire process of CT application review
with the appropriate reasons for approval
or rejection of the application, approval
criteria will be very useful. Transparency
on CT audit, its process will be useful
to build confidence in integrity of the
data coming out of India. Increase in the
number of Government regulated and
funded CT centres, new initiatives for
funding translational science/medicine with
high-quality training in clinical research
management, basic science research and
Quality assurance is very much needed.
Industry exchange programs should be
encouraged at all levels so that Biotech/
pharma/clinical trial experts from developed
regulated regions should be allowed to
come to India to train our CT community
including for regulators vice versa to foster
cross-country collaboration initiatives.
Clinical research professionals including
medical doctors in India need to be
appropriately trained on ethics from the
beginning during medical school. They need
to be educated on the impact of unethical
research on the subject, their family, CT
industry and the country eventually. There
should, not only be ethics courses included
in the curriculum from the beginning, but
also, annual ethics certification for CRAs
and investigators to keep them up to date
with the current regulations, GCPs and
ethical conduct of CTs. CME credit could
be provided to attend these training at
least once or twice a year. People should
own up responsibilities and the attitude of
“Laissez faire” or casual attitude towards
consenting, ethical/quality trials process
including documentation need to go. The
standard of clinical trial should be high
irrespective of to which market this drug will
go and whether the trial is local or global.
Same high ethical and quality ICH GCP
standards should be maintained at all levels
(Sponsors, Investigator, CROs, Regulators,
Ethics committees)
Media holds a key responsibility in the
process too and it is hence critical for the
media to present the right accurate data and
not biased data especially on the CT related
activities, adverse events, deaths and
injuries related to CTs as presented before
in several instances. It is very important
for the regulators, the industry and the
Government to come together and plan the
regulations that protect the interest of the
public at all times but, still have regulations
that are supportive to the industry leading to
the economic growth of the country.

Conclusion
There is an urgent requirement for
readdressing some of the amendments to
continue protecting the interests of subjects
as a priority however, simultaneously
upholding scientific research and
development that will be beneficial to
society. It is critical that clinical research
community at all levels diligently follow the
laws that are in place, understand and apply
the guidelines and create a transparent
trusted environment so that integrity of
the Indian CT industry is maintained. It
is the hope of Indian CT fraternity that
new and reformed regulations once
amended further will be able to bring back
Indian CT industry to the highest global
ethical standards.

Insufficient training or mentoring of young
scientific community on advanced practical
CT activities including practical GCPs is
a real loss to Indian scientific community,
as India could easily become a centre of
basic medical and clinical excellence with a
true Evidence-based Integrative Medicine.
At every level the sponsor, investigator,
monitor, regulator, inspector, CRA, clinical
coordinator, there should be a clear focus
on integrity and quality for India’s CTs
industry to grow. Years may still be required
before further clarity if brought in to address
the current lacuna in the regulation,
quality and ethical standards to effect all
transformations, but it is the hope that this
year forwards will see a tremendous move
forward towards that goal.